Osmotic device containing venlafaxine and an anti-psychotic agent

ABSTRACT

The present invention provides an osmotic device containing controlled release venlafaxine in the core in combination with an anti-psychotic agent in a rapid release external coat. A wide range of anti-psychotic agents can be used in this device. Particular embodiments of the invention provide osmotic devices having predetermined release profiles. One embodiment of the osmotic device includes an external coat that has been spray-coated rather compression-coated onto the device. The device with spray-coated external core is smaller and easier to swallow than the similar device having a compression-coated external coat. The device is useful for the treatment of depression, anxiety or psychosis related disorders.

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

The present application claims the priority of and is a divisional ofU.S. application Ser. No. 09/728,276 filed Nov. 30, 2000, now U.S. Pat.No. 6,572,890 which claims the priority of Provisional Application forPatent No. 60/175,822 filed Jan. 13, 2000.

FIELD OF THE INVENTION

This invention pertains to an osmotic device containing venlafaxine.More particularly, it pertains to an osmotic device tablet that providesa controlled release of venlafaxine, and optionally an anti-psychoticagent, following a particularly advantageous release profile.

BACKGROUND OF THE INVENTION

Clinical depression is a disorder characterized by low self-esteem,guilt, self-reproach, introversion, sadness, despair, sleepingdisorders, eating disorders or discouragement. Depression generallycauses a lower or decrease of a person's function. Anxiety is a disordercharacterized by responses to anticipation of unreal or imagined danger.It manifests itself as increased heart rate, altered respiration rate,sweating, trembling, weakness, or fatigue. Psychosis is a disordercharacterized by gross impairment in reality perception as evidenced bydelusions, hallucinations, markedly incoherent speech, or disorganizedand agitated behavior without apparent awareness on the part of theperson of the incomprehensibility of his behavior.

Major depression and anxiety occur concomitantly in more patients thaneither one alone. When these disorders occur together, they areassociated with more severe symptoms, increased impairment of function,a longer chronic course, poorer outcome, and a higher incidence ofsuicide.

Antidepressants, such as venlafaxine, have been tested for the treatmentof depression and symptoms of anxiety. Anti-psychotic agents, such asrisperidone, are used for the treatment of psychosis. On occasion, aperson suffering from depression or anxiety and psychosis will beprescribed an antidepressant agent and an anti-psychotic agent. Ratherthan administration of two different dosages, it would be useful in theart to have available a single dosage containing both an antidepressantand an anti-psychotic.

Venlafaxine is commercially available in an extended release capsuledosage form from Wyeth Ayerst under the trademark EFFEXOR XR™. Thecapsule is available in 37.5, 75, and 150 mg strengths. The capsule isdisclosed in U.S. Pat. No. 4,535,186 and does not contain thevenlafaxine in combination with an anti-psychotic agent. Moreover, theEFFEXOR XR™ formulation provides an incomplete release of venlafaxine.

Bymaster et al. (European Patent Application No. EP 0830864 A1) disclosea method, and compositions and dosage forms therefor, of treatingpsychoses with a combination of a serotonin uptake inhibitor and ananti-psychotic agent. Bymaster et al. do not disclose an osmotic devicecontaining such combination nor the beneficial effects of sequentialadministration of the two drugs, one rapid release and the othercontrolled release, from a single dosage form.

Controlled release capsule dosage forms and osmotic device dosage formsare generally known by the skilled artisan to provide different releaseprofiles. Effective therapy with antidepressants and anxiolytic agentsis dependent upon a careful control of the blood plasma levels of theseagents, and therefore, upon the release profiles of these agents fromtheir respective dosage forms.

Osmotic devices and other tablet formulations are known for theirability to provide a controlled release of a wide range of drugs. Suchosmotic devices and other tablet formulations are disclosed in U.S. Pat.No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard etal., Argentina Patent No. 234,493, U.S. Pat. No. 4,673,405 to Guittardet al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No.5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770, U.S. Pat. No.6,004,582 to Faour et al., and Argentina Patent No. 199,301, the entiredisclosures of which are hereby incorporated by reference.

These references, however, do not disclose osmotic devices that providethe specific plasma profiles or release profiles for venlafaxine (VFX),and an optional anti-psychotic agent, that the present inventionprovides. Moreover, the prior art does not disclose an osmotic devicecontaining a combination of venlafaxine with an anti-psychotic agent,and generally wherein the venlafaxine and anti-psychotic agent aredelivered according to specific release profiles that are advantageousover known formulations.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides an osmotic devicecomprising:

a core comprising a therapeutically effective amount of venlafaxine andat least one osmotic agent or osmopolymer; and

a semipermeable membrane surrounding the core and having a passagewaythere through;

wherein the core provides a controlled release of VFX, and at least 80%of the VFX is released within 13 hours after exposure of the osmoticdevice to an aqueous solution.

Another aspect of the present invention provides an osmotic device forthe delivery of VFX and an anti-psychotic agent comprising:

a core comprising a therapeutically effective amount of venlafaxine andat least one osmotic agent or osmopolymer;

a semipermeable membrane surrounding the core and having a passagewaythere through; and

an external coat comprising a therapeutically effective amount of ananti-psychotic agent;

wherein the core provides a controlled release of VFX, and at least 80%of the VFX is released within 13 hours after exposure of the osmoticdevice to an aqueous solution, and the external coat provides a rapidrelease of the anti-psychotic agent, and at least 75% of theanti-psychotic agent is released within 1 hour after exposure of theosmotic device to an aqueous solution.

In some embodiments, the external coat is applied by spray coating orcompression coating. By spray coating rather than compression coatingthe external coat, a thinner external coat, and therefore a smallerosmotic device, is formed.

Another aspect of the invention provides a method of treatingdepression, anxiety and/or psychosis in a mammal, the method comprisingthe step of administering an osmotic device which provides a controlledrelease of VFX from its core and a rapid release of an anti-psychoticagent from an external coat, wherein at least 75% of the anti-psychoticagent is released within about 40 minutes, and at least about 60% of theVFX is released within about 12 hours after administration.

In other embodiments, the osmotic device provides: a) a VFX releaseprofile similar to that shown in FIG. 1; or b) a VFX plasma profilesimilar to that shown in FIG. 2 or 4. In still other embodiments, therelease of VFX and/or the anti-psychotic agent has a delayed onset.

In even other embodiments, the anti-psychotic agent is selected from thegroup consisting of risperidone, olanzapine, clozapine, sertindole,ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone,loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine,chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine,lithium, mesoridazine, spiperone, promazine, prochlorperazine,thioridazine, thiothixene, triflupromazine, and raclopride.

In yet other embodiments, the following anti-psychotic agents areadministered in the indicated doses: a) risperidone—5 to 10 mg per day;b) olanzapine—5 to 20 mg, 0.25–50 mg, 1–30 mg, or 1–25 mg per day; c)clozapine—100 to 400 mg, 12.5–900 mg, or 150–450 mg per day; d)sertindole—15 to 20 mg per day or 0.0001 to 1.0 mg/kg of body weight perday; e) ziprasidone—80 to 160 mg, 5 to 500 mg or 50 to 100 mg per day;f) quetiapine—150 to 600 mg or 1.0–40 mg/kg of body weight per day; g)sulpiride—50 to 100 mg per day; h) pimozide—2 to 4 mg per day; or i)clothiapine—40 mg per day.

The venlafaxine, as either its free base or salt form, will beadministered once daily in doses ranging form about 10 to 150 mg, 25 to125 mg, 150 to 300 mg, or 10–500 mg.

The osmotic device generally delivers the anti-psychotic agent to theupper GI tract and the venlafaxine to the middle to lower GI tract.

Other features, advantages and embodiments of the invention will becomeapparent to those skilled in the art by the following description,accompanying examples.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are part of the present specification and areincluded to further demonstrate certain aspects of the invention. Theinvention may be better understood by reference to one or more of thesedrawings in combination with the detailed description of the specificembodiments presented herein.

FIG. 1 depicts an in vitro release profile for VFX from the exemplaryformulation of Example 1.

FIG. 2 depicts an in vivo plasma profile for VFX from the exemplaryformulation of Example 1.

FIG. 3 depicts an in vivo plasma profile for the commercial productEFFEXOR ER.

FIG. 4 depicts a comparative plot including the plasma profiles of FIGS.2 and 3.

DETAILED DESCRIPTION OF THE INVENTION

Venlafaxine and anti-psychotic agents are available from a large numberof commercial sources. The invention provides for the administration ofvenlafaxine alone or in combination with an anti-psychotic agent,wherein these compounds are in their free base, free acid, racemic,optically pure, diastereomeric and/or pharmaceutically acceptable saltforms.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the therapeutic compound is modifiedby making acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of the VFX or anti-psychotic agent. The pharmaceuticallyacceptable salts include the conventional non-toxic salts, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as amino acids, acetic, propionic, succinic, glycolic,stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like. Lists of suitable saltsare found in Remington's Pharmaceutical Sciences, 17th ed., MackPublishing Company, Easton, Pa., 1985, p. 1418, the disclosure of whichis hereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

FIG. 1 depicts various venlafaxine in vitro release profiles for theosmotic device tablets described in Example 1 (average of 6 runs). Thisformulation exhibits a 22-hour or greater controlled release of VFX. TheVFX release profile of this exemplary formulation is generally describedas follows:

Time (h) Maximum Percent Released Minimum Percent Released 1 9.0 5.6 324.1 22.8 5 46.6 41.0 7 62.7 55.9 9 72.9 66.6 11 79.0 73.9 13 83.4 78.615 86.6 81.8 19 90.1 86.3 23 ≧92.9 89.0

The venlafaxine release profile can also be described as follows:

Time (h) Released (%) STD (%) 1 7.2 1.3 3 23.6 0.5 5 43.3 2.1 7 59.0 2.39 69.7 2.1 11 77.0 1.8 13 81.8 1.7 15 84.7 1.7 19 88.1 1.4 23 ≧90.8 1.5

FIG. 2. Depicts an VFX in vivo plasma profile for the osmotic devicetablets described in Example 1 (mean±S.D., n=12 runs). This exemplarydevice provides terapeutically effective levels of VFX between theperiod of about 1 to about 36 hours after administration. TherapeuticVFX plasma concentration levels range from about 2 to about 37 ng/ml,generally about 2 to about 22 ng/ml. The mean C_(max) is about 19 ng ofVFX per ml of plasma at about 8–10 hours after administration. The invivo plasma profile can be characterized as follows:

Time after Administration Mean VFX Plasma (h) Concentration (ng/ml)S.E.M. 0 0.0 0.0 0.5 0.3 0.2 1 0.4 0.2 2 3.2 0.8 4 13.9 2.6 6 17.5 2.5 818.7 2.7 10 18.8 2.9 12 16.7 2.5 14 15.8 2.7 16 11.8 2.0 20 8.6 1.7 246.6 1.1 28 5.7 1.5 32 3.4 0.7 36 2.2 0.5 48 1.7 0.5 SD denotes “standarddeviation”.

The osmotic device generally provides the above-described plasma profileafter administration of a single daily dose, i.e. acute dosing. Theartisan of ordinary skill will understand that chronic daily dosing ofthe osmotic device will generally result in a relatively flat plasmaprofile over a 24-hour period for venlafaxine and optionally theanti-psychotic agent, since a steady-state or equilibrium will bereached due to chronic administration.

FIG. 3. depicts an VFX in vivo plasma profile for the EFFEXOR ER 75 mgproduct (mean±S.D., n=12). The mean C_(max) for the commercial productis about 23 ng of VFX per ml of plasma at about 8–10 hours afteradministration. FIG. 4 depicts comparative data for the in vivo VFX ofthe formulations of the invention and of the commercial product. Thedata shows absolute differences in the C_(max) and T_(max) valuesachieved.

Calculated PK parameters Bioequivalence evaluation REF Geometric mean90% Example 1 (EFFEXOR ® Relative Confidence Bioequivalence Parameter(75 mg) ER 75 mg) bioavailability % Interval Limits ABC∞ (ng · h/ml)388.8 ± 64.4 398.5 ± 71.6 99.4  92.2–102.9 80–120 C_(max) (ng/ml) 20.4 ±2.8 23.4 ± 3.3 87.8 81.9–92.9 80–120 C_(max)/ABC∞  0.057 ± 0.004  0.064± 0.005 88.5 82.8–93.2 80–120 t_(max) (h)  9.0 ± 2.0  6.0 ± 2.5 — — — Ke(h⁻¹)  0.077 ± 0.007  0.079 ± 0.010 — — —

The release profile of the osmotic device of the invention is preferredas it provides a lower C_(max) and longer T_(max) while at the same timemaintaining therapeutically effective levels thereof over an extendedperiod of time.

Depending upon the particular combination of ingredients used to preparethe osmotic device, it will generally provide an expected overallvenlafaxine release profile resembling a pseudo-first order,first-order, pseudo-second order, second order, pseudo-third order orthird order release profile.

All of the tablet formulations of the invention will providetherapeutically effective levels of venlafaxine and an anti-psychoticagent for at least a predetermined period of time. The tablets of theinvention will generally provide therapeutically effective amounts ofvenlafaxine for a total time period of not less than 18 hours and notmore than 30 hours, generally not less than 20 hours and not more than24 hours, or not less than 22 hours.

The external coating can be an immediately dissolving coating thatdissolves in the buccal cavity or a rapidly dissolving coating thatdissolved in the stomach, jejunum or duodenum. The controlled releasecore generally begins to release venlafaxine within about 2 hours afteradministration.

The rapid release coating will release all of its anti-psychotic agentwithin three hours after administration and preferably at least 75% ofits anti-psychotic agent within about 40 minutes after administration.While the anti-psychotic agent is released over a short period of time,the therapeutic benefit that it provides will last at least 12 hours andgenerally up to about 24 hours. The actual time period will varyaccording to the anti-psychotic agent used and, in particular, itshalf-life in a patient.

Those of ordinary skill in the art will appreciate that the particularamounts of venlafaxine and anti-psychotic agent used in the osmoticdevice will vary according to, among other things, the desiredpharmacokinetic behavior in a mammal.

When a rapidly dissolving coat is used in the tablet formulations of theinvention, the coat will generally comprise an inert and non-toxicmaterial that is at least partially, and generally substantiallycompletely, soluble or erodible in an environment of use. The rapidlydissolving coat will be soluble in the buccal cavity and/or upper GItract, such as the stomach, duodenum, jejunum or upper small intestines.Exemplary materials are disclosed in U.S. Pat. Nos. 4,576,604 and4,673,405, and the text Pharmaceutical Dosage Forms: Tablets Volume I,Second Edition. A. Lieberman. ed. 1989, Marcel Dekker, Inc. the relevantdisclosures of which are hereby incorporated by reference. Inembodiments, the rapidly dissolving coat will be soluble in saliva,gastric juices, or acidic fluids.

The long acting controlled release tablet formulations that provide adelayed and sustained release of venlafaxine may include an enteric coatthat is soluble or erodible in intestinal juices, substantially pHneutral or basic fluids but for the most part insoluble in gastricjuices or acidic fluids. A wide variety of other polymeric materials areknown to possess these various solubility properties. Such otherpolymeric materials include, by way of example and without limitation,cellulose acetate phthalate (CAP), cellulose acetate trimelletate (CAT),poly(vinyl acetate) phthalate (PVAP), hydroxypropyl methylcellulosephthalate (HP), poly(methacrylate ethylacrylate) (1:1) copolymer(MA-EA), poly(methacrylate methylmethacrylate) (1:1) copolymer (MA-MMA),poly(methacrylate methylmethacrylate) (1:2) copolymer, Eudragit L-30-D™(MA-EA, 1:1), Eudragit™ L-100–55™ (MA-EA, 1:1), hydroxypropylmethylcellulose acetate succinate (HPMCAS), Coateric™ (PVAP), Aquateric™(CAP), AQUACOAT™ (HPMCAS) and combinations thereof. The enteric coat canalso comprise dissolution aids, stability modifiers, and bioabsorptionenhancers.

When the enteric coat is intended to be dissolved, eroded or becomedetached from the core in the colon, materials such ashydroxypropylcellulose, microcrystalline cellulose (MCC, Avicel™ fromFMC Corp.), poly (ethylene-vinyl acetate) (60:40) copolymer (EVAC fromAldrich Chemical Co.), 2-hydroxyethylmethacrylate (HEMA), MMA,terpolymers of HEMA: MMA:MA synthesized in the presence ofN,N′-bis(methacryloyloxyethyloxycarbonylamino)—azobenzene, azopolymers,enteric coated timed release system (Time Clock® from PharmaceuticalProfiles, Ltd., UK) and calcium pectinate can be used.

A polymeric material for use in the enteric coat involves entericmaterials that resist the action of gastric fluid avoiding permeationthrough the semipermeable wall while one or more of the materials in thecore of the tablet are solubilized in the intestinal tract therebyallowing delivery of the venlafaxine in the core by osmotic pumping inan osmotic device to begin. A material that easily adapts to this kindof requirement is a poly(vinylpyrrolidone)-vinyl acetate copolymer, suchas the material supplied by BASF under its Kollidon VA64 trademark,mixed with magnesium stearate and other similar excipients. The entericcoat can also comprise povidone, which is supplied by BASF under itsKollidon K 30 trademark, and hydroxypropyl methylcellulose, which issupplied by Dow under its Methocel E-15 trademark. The materials can beprepared in solutions of having different concentrations of polymeraccording to the desired solution viscosity. For example, a 10% P/Vaqueous solution of Kollidon K 30 has a viscosity of about 5.5–8.5 cpsat 20° C., and a 2% P/V aqueous solution of Methocel E-15 has aviscosity of about 13–18 cps at 20° C.

The enteric coat can comprise one or more materials that do notdissolve, disintegrate, or change their structural integrity in thestomach and during the period of time that the tablet resides in thestomach. Representative materials that keep their integrity in thestomach can comprise a member selected from the group consisting of (a)keratin, keratin sandarac-tolu, salol (phenyl salicylate), salolbeta-naphthylbenzoate and acetotannin, salol with balsam of Peru, salolwith tolu, salol with gum mastic, salol and stearic acid, and salol andshellac; (b) a member selected from the group consisting of formalizedprotein, formalized gelatin, and formalized cross-linked gelatin andexchange resins; (c) a member selected from the group consisting ofmyristic acid-hydrogenated castor oil-cholesterol, stearic acid-muttontallow, stearic acid-balsam of tolu, and stearic acid-castor oil; (d) amember selected from the group consisting of shellac, ammoniatedshellac, ammoniated shellac-salol, shellac-wool fat, shellac-acetylalcohol, shellac-stearic acid-balsam of tolu, and shellac n-butylstearate; (e) a member selected from the group consisting of abieticacid, methyl abictate, benzoin, balsam of tolu, sandarac, mastic withtolu, and mastic with tolu, and mastic with acetyl alcohol; (f) acrylicresins represented by anionic polymers synthesized from methacrylateacid and methacrylic acid methyl ester, copolymeric acrylic resins ofmethacrylic and methacrylic acid and methacrylic acid alkyl esters,copolymers of alkacrylic acid and alkacrylic acid alkyl esters, acrylicresins such asdimethylaminoethylmethacrylate-butylmethacrylate-methylmethacrylatecopolymer of 150,000 molecular weight, methacrylicacid-methylmethacrylate 50:50 copolymer of 135,000 molecular weight,methacrylic acid-methylmethacrylate-30:70-copolymer of 135,000 mol. wt.,methacrylic acid-dimethylaminoethyl-methacrylate-ethylacrylate of750,000 mol. wt., methacrylic acid-methylmethacrylate-ethylacrylate of1,000,000 mol. wt., and ethylacrylate-methylmethacrylate-ethylacrylateof 550,000 mol. wt; and, (g) an enteric composition comprising a memberselected from the group consisting of cellulose acetyl phthalate,cellulose diacetyl phthalate, cellulose triacetyl phthalate, celluloseacetate phthalate, hydroxypropyl methylcellulose phthalate, sodiumcellulose acetate phthalate, cellulose ester phthalate, cellulose etherphthalate, methylcellulose phthalate, cellulose ester-ether phthalate,hydroxypropyl cellulose phthalate, alkali salts of cellulose acetatephthalate, alkaline earth salts of cellulose acetate phthalate, calciumsalt of cellulose acetate phthalate, ammonium salt of hydroxypropylmethylcellulose phthalate, cellulose acetate hexahydrophthalate,hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetatephthalate diethyl phthalate, dibutyl phthalate, dialkyl phthalatewherein the alkyl comprises from 1 to 7 straight and branched alkylgroups, aryl phthalates, and other materials known to one or ordinaryskill in the art.

The semipermeable membrane of the osmotic device is formed of a materialthat is substantially permeable to the passage of fluid from theenvironment of use to the core and substantially impermeable to thepassage of active agent from the core. Many common materials known bythose of ordinary skill in the art are suitable for this purpose.Exemplary materials are cellulose esters, cellulose ethers and celluloseesters-ethers. However, it has been found that a semipermeable membraneconsisting essentially of cellulose acetate (CA) and poly(ethyleneglycol) (PEG), in particular PEG 400, are when used in combination withthe other materials required in the present osmotic device. Thisparticular combination of CA and PEG provides a semipermeable membranethat gives the osmotic device a well controlled release profile for theactive agent in the core and that retains its chemical and physicalintegrity in the environment of use. The ratio of CA:PEG generallyranges from about 50–99% by weight of CA: about 50–1% by weight of PEG,and generally about 95% by weight of CA: about 5% by weight of PEG. Theratio can be varied to alter permeability and ultimately the releaseprofile of the osmotic device. Other materials can include a selectedmember of the group of cellulose acylates such as cellulose acetate,cellulose diacetate, cellulose triacetate and combinations thereof. Manysuitable polymers, include those disclosed in Argentine Patent No.199,301 and other references cited herein, the disclosures of which arehereby incorporated by reference.

The core of the osmotic device tablet of the present invention willcomprise venlafaxine, at least one pharmaceutically acceptable excipientand optionally one or more other materials. Generally, the tabletformulations will comprise about 0.1–99.9% by weight of venlafaxine inthe uncoated tablet core. Ranges will vary according to theanti-psychotic agent used and the intended use of the osmotic device.

When the controlled release tablet is an osmotic device, osmoticallyeffective solutes, osmotic agents or osmagents are added. Theseosmagents can aid in either the suspension or dissolution of the VFX inthe core. Exemplary osmagents include organic and inorganic compoundssuch as salts, acids, bases, chelating agents, sodium chloride, lithiumchloride, magnesium chloride, magnesium sulfate, lithium sulfate,potassium chloride, sodium sulfite, calcium bicarbonate, sodium sulfate,calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid,raffinose, sucrose, alpha-d-lactose monohydrate, glucose, combinationsthereof and other similar or equivalent materials which are widely knownin the art. Osmagents can also be incorporated to the core of theosmotic device to control the release of VFX therefrom.

The tablets of the invention can also comprise an acidifying agent,alkalizing agent, adsorbent, antioxidant, buffering agent, colorant,flavorant, sweetening agent, tablet antiadherent, tablet binder, tabletand capsule diluent, tablet direct compression excipient, tabletdisintegrant, tablet glidant, tablet lubricant, tablet or capsuleopaquant and/or tablet polishing agents.

As used herein, the term “adsorbent” is intended to mean an agentcapable of holding other molecules onto its surface by physical orchemical (chemisorption) means. Such compounds include, by way ofexample and without limitation, powdered and activated charcoal andother materials known to one of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by the oxidative process. Such compounds include, by way ofexample and without limitation, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid,monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite,sodium formaldehyde sulfoxylate and sodium metabisulfite and othermaterials known to one of ordinary skill in the art.

As used herein, the term “alkalizing agent” is intended to mean acompound used to provide alkaline medium for product stability. Suchcompounds include, by way of example and without limitation, ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodiumbicarbonate, sodium hydroxide, triethanolamine, and trolamine and othersknown to those of ordinary skill in the art.

As used herein, the term “acidifying agent” is intended to mean acompound used to provide an acidic medium for product stability. Suchcompounds include, by way of example and without limitation, aceticacid, amino acid, citric acid, fumaric acid and other alpha hydroxyacids, such as hydrochloric acid, ascorbic acid, and nitric acid andothers known to those of ordinary skill in the art.

As used herein, the term “buffering agent” is intended to mean acompound used to resist change in pH upon dilution or addition of acidor alkali. Such compounds include, by way of example and withoutlimitation, potassium metaphosphate, potassium phosphate, monobasicsodium acetate and sodium citrate anhydrous and dihydrate and othermaterials known to one of ordinary skill in the art.

As used herein, the term “sweetening agent” is intended to mean acompound used to impart sweetness to a preparation. Such compoundsinclude, by way of example and without limitation, aspartame, dextrose,glycerin, mannitol, saccharin sodium, sorbitol and sucrose and othermaterials known to one of ordinary skill in the art.

As used herein, the term “tablet antiadherent” is intended to mean anagent which prevent the sticking of tablet formulation ingredients topunches and dies in a tableting machine during production. Suchcompounds include, by way of example and without limitation, magnesiumstearate, talc, calcium stearate, glyceryl behenate, PEG, hydrogenatedvegetable oil, mineral oil, stearic acid and other materials known toone of ordinary skill in the art.

As used herein, the term “tablet binder” is intended to mean a substanceused to cause adhesion of powder particles in table granulations. Suchcompounds include, by way of example and without limitation, acacia,alginic acid, carboxymethylcellulose sodium, poly(vinylpyrrolidone),compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquidglucose, methylcellulose, povidone and pregelatinized starch and othermaterials known to one of ordinary skill in the art.

When needed, binders may also be included in the tablets. Exemplarybinders include acacia, tragacanth, gelatin, starch, cellulose materialssuch as methyl cellulose and sodium carboxy methyl cellulose, alginicacids and salts thereof, polyethylene glycol, guar gum, polysaccharide,bentonites, sugars, invert sugars, poloxamers (PLURONIC F68, PLURONICF127), collagen, albumin, gelatin, cellulosics in nonaqueous solvents,combinations thereof and the like. Other binders include, for example,polypropylene glycol, polyoxyethylene-polypropylene copolymer,polyethylene ester, polyethylene sorbitan ester, polyethylene oxide,combinations thereof and other materials known to one of ordinary skillin the art.

As used herein, the term “tablet and capsule diluent” or “filler” isintended to mean inert substances used as fillers to create the desiredbulk, flow properties, and compression characteristics in thepreparation of tablets and capsules. Such compounds include, by way ofexample and without limitation, dibasic calcium phosphate, kaolin,lactose, sucrose, mannitol, microcrystalline cellulose, powderedcellulose, precipitated calcium carbonate, sorbitol, and starch andother materials known to one of ordinary skill in the art.

As used herein, the term “tablet direct compression excipient” isintended to mean a compound used in direct compression tabletformulations. Such compounds include, by way of example and withoutlimitation, dibasic calcium phosphate (e.g., Ditab) and other materialsknown to one of ordinary skill in the art.

As used herein, the term “tablet glidant” is intended to mean agentsused in tablet and capsule formulations to reduce friction during tabletcompression. Such compounds include, by way of example and withoutlimitation, colloidal silica, cornstarch, talc, calcium silicate,magnesium silicate, colloidal silicon, silicon hydrogel and othermaterials known to one of ordinary skill in the art.

As used herein, the term “tablet lubricant” is intended to meansubstances used in tablet formulations to reduce friction during tabletcompression. Such compounds include, by way of example and withoutlimitation, calcium stearate, magnesium stearate, mineral oil, stearicacid, and zinc stearate and other materials known to one of ordinaryskill in the art.

As used herein, the term “tablet/capsule opaquant” is intended to mean acompound used to render a capsule or a tablet coating opaque. May beused alone or in combination with a colorant. Such compounds include, byway of example and without limitation, titanium dioxide and othermaterials known to one of ordinary skill in the art.

As used herein, the term “tablet polishing agent” is intended to mean acompound used to impart an attractive sheen to coated tablets. Suchcompounds include, by way of example and without limitation, carnaubawax, and white wax and other materials known to one of ordinary skill inthe art.

As used herein, the term “tablet disintegrant” is intended to mean acompound used in solid dosage forms to promote the disruption of thesolid mass into smaller particles which are more readily dispersed ordissolved. Exemplary disintegrants include, by way of example andwithout limitation, starches such as corn starch, potato starch,pre-gelatinized and modified starches thereof, sweeteners, clays, suchas bentonite, microcrystalline cellulose(e.g., Avicel),carboxymethylcellulose calcium, cellulose polyacrilin potassium (e.g.,Amberlite), alginates, sodium starch glycolate, gums such as agar, guar,locust bean, karaya, pectin, tragacanth and other materials known to oneof ordinary skill in the art.

As used herein, the term “colorant” is intended to mean a compound usedto impart color to solid (e.g., tablets) pharmaceutical preparations.Such compounds include, by way of example and without limitation, FD&CRed No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&CGreen No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide,red, other F.D. & C. dyes and natural coloring agents such as grape skinextract, beet red powder, beta-carotene, annato, carmine, turmeric,paprika, and other materials known to one of ordinary skill in the art.The amount of coloring agent used will vary as desired.

As used herein, the term “flavorant” is intended to mean a compound usedto impart a pleasant flavor and often odor to a pharmaceuticalpreparation. Exemplary flavoring agents or flavorants include syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereof.These may also include cinnamon oil, oil of wintergreen, peppermintoils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaveoil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.Other useful flavors include vanilla, citrus oil, including lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot andso forth. Flavors which have been found to be particularly usefulinclude commercially available orange, grape, cherry and bubble gumflavors and mixtures thereof. The amount of flavoring may depend on anumber of factors, including the organoleptic effect desired. Flavorswill be present in any amount as desired by those of ordinary skill inthe art. Particular flavors are the grape and cherry flavors and citrusflavors such as orange.

The present tablets can also employ one or more commonly known surfaceactive agents or cosolvents that improve wetting or disintegration ofthe tablet core or layers.

Plasticizers can also be included in the tablets to modify theproperties and characteristics of the polymers used in the coats or coreof the tablets. As used herein, the term “plasticizer” includes allcompounds capable of plasticizing or softening a polymer or binder usedin invention. The plasticizer should be able to lower the meltingtemperature or glass transition temperature (softening pointtemperature) of the polymer or binder. Plasticizers, such as lowmolecular weight PEG, generally broaden the average molecular weight ofa polymer in which they are included thereby lowering its glasstransition temperature or softening point. Plasticizers also generallyreduce the viscosity of a polymer. It is possible the plasticizer willimpart some particularly advantageous physical properties to the osmoticdevice of the invention.

Plasticizers useful in the invention can include, by way of example andwithout limitation, low molecular weight polymers, oligomers,copolymers, oils, small organic molecules, low molecular weight polyolshaving aliphatic hydroxyls, ester-type plasticizers, glycol ethers,poly(propylene glycol), multi-block polymers, single block polymers, lowmolecular weight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol and glycerin. Such plasticizers can alsoinclude ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, diethylene glycol, triethylene glycol, tetraethyleneglycol and other poly(ethylene glycol) compounds, monopropylene glycolmonoisopropyl ether, propylene glycol monoethyl ether, ethylene glycolmonoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate,ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate,acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,tributyl citrate and allyl glycolate. All such plasticizers arecommercially available from sources such as Aldrich or Sigma ChemicalCo. It is also contemplated and within the scope of the invention, thata combination of plasticizers may be used in the present formulation.The PEG based plasticizers are available commercially or can be made bya variety of methods, such as disclosed in Poly(ethylene glycol)Chemistry: Biotechnical and Biomedical Applications (J. M. Harris, Ed.;Plenum Press, NY) the disclosure of which is hereby incorporated byreference.

The tablets of the invention can also include oils, for example, fixedoils, such as peanut oil, sesame oil, cottonseed oil, corn oil and oliveoil; fatty acids, such as oleic acid, stearic acid and isotearic acid;and fatty acid esters, such as ethyl oleate, isopropyl myristate, fattyacid glycerides and acetylated fatty acid glycerides. It can also bemixed with alcohols, such as ethanol, isopropanol, hexadecyl alcohol,glycerol and propylene glycol; with glycerol ketals, such as2,2-dimethyl-1,3-dioxolane4-methanol; with ethers, such aspoly(ethyleneglycol) 450, with petroleum hydrocarbons, such as mineraloil and petrolatum; with water, or with mixtures thereof; with orwithout the addition of a pharmaceutically suitable surfactant,suspending agent or emulsifying agent.

Soaps and synthetic detergents may be employed as surfactants and asvehicles for detergent compositions. Suitable soaps include fatty acidalkali metal, ammonium, and triethanolamine salts. Suitable detergentsinclude cationic detergents, for example, dimethyl dialkyl ammoniumhalides, alkyl pyridinium halides, and alkylamine acetates; anionicdetergents, for example, alkyl, aryl and olefin sulfonates, alkyl,olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionicdetergents, for example, fatty amine oxides, fatty acid alkanolamides,and poly(oxyethylene)-block-poly(oxypropylene) copolymers; andamphoteric detergents, for example, alkyl β-aminopropionates and2-alkylimidazoline quaternary ammonium salts; and mixtures thereof.

Various other components, not otherwise listed above, can be added tothe present formulation for optimization of a desired active agentrelease profile including, by way of example and without limitation,glycerylmonostearate, nylon, cellulose acetate butyrate, d,1-poly(lactic acid), 1,6-hexanediamine, diethylenetriamine, starches,derivatized starches, acetylated monoglycerides, gelatin coacervates,poly (styrene-maleic acid) copolymer, glycowax, castor wax, stearylalcohol, glycerol palmitostearate, poly(ethylene), poly(vinyl acetate),poly(vinyl chloride), 1,3-butylene-glycoldimethacrylate,ethyleneglycol-dimethacrylate and methacrylate hydrogels.

It should be understood, that compounds used in the art ofpharmaceutical formulation generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

By the term “effective amount”, it is understood that, with respect to,for example, pharmaceuticals, a therapeutically effective amount iscontemplated. A therapeutically effective amount is the amount orquantity of venlafaxine which is sufficient to elicit the required ordesired therapeutic response, or in other words, the amount which issufficient to elicit an appreciable biological response whenadministered to a patient.

The tablets (osmotic devices) of the invention can assume any shape orform known in the art of pharmaceutical sciences. The device of theinvention can be a pill, sphere, tablet, bar, plate, paraboloid ofrevolution, ellipsoid of revolution or the like. The tablets can alsoinclude surface markings, cuttings, grooves, letters and/or numerals forthe purposes of decoration, identification and/or other purposes.

The tablets (osmotic devices) of the invention can be prepared accordingto the methods disclosed herein or those well known in the art, morespecifically according to the methods disclosed in the disclosureincorporated herein by reference. For example, according to onemanufacturing technique, venlafaxine and excipients that comprise thecore are mixed in solid, semisolid or gelatinous form, then moistenedand sieved through a specified screen to obtain uncoated cores. Theuncoated cores are then dried in a dryer and compressed, for example, bypunching. The compressed and uncoated cores are then covered with asemipermeable membrane. Subsequently, the semipermeable membranesurrounding the core should be perforated with, for example, laserequipment. Finally, an external coat containing the anti-psychotic agentis applied to the semipermeable membrane.

The external coat can be applied as a compression coating, but it isgenerally applied as a sprayed coating. The sprayed coating is thinnerand lighter than the compression coating, and an osmotic deviceincluding the sprayed on external coating is, therefore, smaller than asimilar osmotic device having a compression coat. A smaller size osmoticdevice generally results in increased patient compliance in taking theosmotic device and is therefore advantageous.

The tablets (osmotic devices) of the invention can be coated with afinish coat as is commonly done in the art to provide the desired shine,color, taste or other aesthetic characteristics. Materials suitable forpreparing the finish coat are well known in the art and found in thedisclosures of many of the references cited and incorporated byreference herein.

The osmotic device of the invention comprises at least one passageway(pore, hole, or aperture) which communicates the exterior of thesemipermeable wall with the core of the device. The passageway can beformed according to any of the known methods of forming passageways in asemipermeable membrane. Such methods include, for example, 1) drilling ahole through the semipermeable membrane with a bit or laser; 2)including a water soluble material within the composition that forms thesemipermeable membrane such that a pore forms when the osmotic device isin an aqueous environment of use; 3) punching a hole through thesemipermeable membrane; or 4) employing a tablet punch having a pin topunch a hole through the semipermeable lamina. The passageway can passthrough the semipermeable wall and one or more of any other laminacoated onto the semipermeable membrane or between the semipermeablemembrane and the core. The passageway(s) can be shaped as desired. Insome embodiments, the passageway is laser drilled and is shaped as anoval, ellipse, slot, slit, cross or circle.

Methods of forming passageways in semipermeable membranes of osmoticdevices are disclosed in U.S. Pat. No. 4,088,864 to Theeuwes et al.,U.S. Pat. No. 4,016,880 to Theeuwes et al., U.S. Pat. No. 3,916,899 toTheeuwes et al., U.S. Pat. No. 4,285,987 to Ayer et al., U.S. Pat. No.4,783,337 to Wong et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S.Pat. No. 4,801,461 to Hamel et al., and U.S. Pat. No. 3,845,770 toTheeuwes et al., the disclosures of which are hereby incorporated byreference.

The preformed passageway, e.g., one made by mechanical means, is formedafter the semipermeable membrane is applied to the core. It can beformed either before or after the inert water soluble coat and/ordrug-containing external coat is applied to the semipermeable membrane.

The advantages of the present system over known systems foradministering venlafaxine in combination with an anti-psychotic agent isimproved therapeutic benefit, simplified manufacturing, and increasedpatient compliance. Moreover, the present formulation will provide anenhanced therapeutic effect when compared to the administration ofvenlafaxine alone.

By administration of the venlafaxine in a controlled release fashion andthe anti-psychotic agent in a rapid release fashion, the osmotic deviceunexpectedly provides an improved pharmacological profile includingreduced side effects, lower drug requirement and/or enhanced therapeuticbenefit as compared to other known methods or dosage forms.

The osmotic device of the invention is useful for treating a variety ofpsychological disorders. The osmotic device can be used to treatpsychotic conditions and mild anxiety with the atypical anti-psychoticswithout the concomitant weight gain typically observed with suchtreatment, conferring a marked and unexpected benefit on the patient.The present invention furthermore provides a potentiation of theincrease in the concentration of norepinephrine observed as an effect ofadministration of a first component compound, by administration of asecond component compound.

The present invention is particularly suited for use in the treatment ofbipolar disorders, mania (mixed state), schizoaffective disorderscharacterized by the occurrence of a depressive episode during theperiod of illness, and depression with psychotic features. Suchdisorders may often be resistant to treatment with an anti-psychoticalone.

The present invention is also useful for the treatment of premenstrualsyndrome (PMS) and anorexia nervosa. Furthermore, the present inventionis useful for the treatment of the agression/violence which may beassociated with certain disorders. These disorders include, but are notlimited to, mania, schizophrenia, schizoaffective disorders, substanceabuse, head injury, and mental retardation.

Psychotic conditions to be treated by the present osmotic deviceinclude, for example, schizophrenia, schizophreniform diseases, acutemania, schizoaffective disorders, and depression with psychoticfeatures. The titles given these conditions represent multiple diseasestates. The following list illustrates a number of these disease states,many of which are classified in the Diagnostic and Statistical Manual ofMental Disorders, 4th Edition, published by the American PsychiatricAssociation (DSM). The DSM code numbers for these disease states aresupplied below, when available, for the convenience of the reader:Paranoid Type Schizophrenia 295.30; Disorganized Type Schizophrenia295.10; Catatonic Type Schizophrenia 295.20; Undifferentiated TypeSchizophrenia 295.90; Residual Type Schizophrenia 295.60;Schizophreniform Disorder 295.40; Schizoaffective Disorder 295.70;Schizoaffective Disorder of the Depressive Type; and Major DepressiveDisorder with Psychotic Features 296.24, 296.34.

Psychoses are often associated with other diseases and conditions, orcaused by such other conditions. For example, they are associated withneurological conditions, endocrine conditions, metabolic conditions,fluid or electrolyte imbalances, hepatic or renal diseases, andautoimmune disorders with central nervous system involvement. Psychosesmay also be associated with use or abuse of certain substances. Thesesubstances include, but are not limited to cocaine, methylphenidate,dexamethasone, amphetamine and related substances, cannabis,hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnoticsand anxiolytics. Psychotic disorders may also occur in association withwithdrawal from certain substances. These substances include, but arenot limited to, sedatives, hypnotics and anxiolytics. The embodiments ofthe present invention are useful for treatment of psychotic conditionsassociated with any of these conditions.

The following examples should not be considered exhaustive, but merelyillustrative of only a few of the many embodiments contemplated by thepresent invention. The methods described herein can be followed toprepare osmotic devices according to the invention.

EXAMPLE 1

A scale batch of Venlafaxine HCl 75 mg was prepared by mixing 84.86 g ofVenlafaxine HCl, 238.83 g of Mannitol and 25.0 g of Povidone. Themixture was wetting with a blend of 120.00 ml of alcohol 96°, 22.31 g ofPolyethylene Glycol 6000 and 1.50 g of Polyethylene Glycol 400. Theblend was granulated and dried at 40–50° C. for 3 hours; then, it wasscreened and mixed with 3.00 g of Colloidal Silicon Dioxide. The blendwas mixed to homogenize and 4.50 g of Magnesium Stearate was added aslubricant. The final blend was tabletted using biconcaves, 9.25-mmdiameter punches. Cores weight: 380.0 mg. Hardness from 7 to 12 kp.

A first composition to cover the cores was prepared as follows: 7.53 gof Copolyvidone, 10,50 g of hydroxypropyl methylcellulose 2910, 3.00 gof Polyethylene Glycol 6000 and 3.97 g of Titanium Dioxide in IsopropylAlcohol.

This polymer mixture was sprayed onto the tablets in a conventional pancoater to obtain film-coated tablets whose membrane coating weighed 25mg approximately. A second composition to cover the film-coated tabletswas prepared as follows: 27.93 g of Cellulose Acetate and 1.47 g ofPolyethylene Glycol 400 in a mixture of 495.0 ml of Methylene Chlorideand 125.0 ml of Methyl Alcohol. This polymer mixture was sprayed ontothe tablets in a conventional pan coater to obtain film-coated tabletswhose membrane coating weighed 29.4 mg approximately. A 0.50-mm hole wasdrilled through the coating in one face of the tablet.

The final coating was prepared by mixing 9,45 g of hydroxypropylmethylcellulose 2910, 6.78 g of Copolyvidone, 2.70 g of PolyethyleneGlycol 6000, 3.20 g of Titanium Dioxide, 90.00 mg of Aluminum LakeQuinoline Yellow and 5.40 mg of Aluminum Lake Sunset Yellow in a mixtureof Methylene Chloride-Alcohol 96° 70:30 v/v (volume/volume). Thispolymer mixture was sprayed onto the tablets in a conventional pancoater to obtain film-coated tablets whose membrane coating weighed 15mg approximately.

Tablets made according to the above procedure will generally have thefollowing composition.

INGREDIENT 37.5 mg 75 mg 150 mg CORE Venlafaxine Hydrochloride 42.430 mg84.860 mg 169.720 mg Mannitol 119.415 mg 238.830 mg 477.660 mg Povidone12.500 mg 25.00 mg 50.000 mg Polyethylene Glycol 400 0.750 mg 1.500 mg3.000 mg Colloidal Silicon Dioxide 1.500 mg 3.000 mg 6.000 mgPolyethylene Glycol 6000 11.155 mg 22.310 mg 44.620 mg MagnesiumStearate 2.250 mg 4.500 mg 9.000 mg COATING A Copolyvidone 5.420 mg7.530 mg 11.930 mg Hydroxypropyl 7.560 mg 10.500 mg 16.630 mgmethylcellulose 2910 Polyethylene Glycol 6000 2.160 mg 3.000 mg 4.750 mgTitanium Dioxide 2.860 mg 3.970 mg 6.290 mg COATING B Cellulose Acetate23.040 mg 27.930 mg 60.440 mg Polyethylene Glycol 400 1.210 mg 1.470 mg4.130 mg COATING C Hydroxypropyl 3.150 mg 6.300 mg 10.080 mgmethylcellulose 2910 Copolyvidone 2.260 mg 4.520 mg 7.230 mgPolyethylene Glycol 6000 0.900 mg 1.800 mg 2.880 mg Titanium Dioxide1.158 mg 2.136 mg 3.709 mg Aluminum Lake Quinoline 0.030 mg 0.060 mg0.095 mg Yellow Aluminum Lake Sunset 0.0018 mg 0.0036 mg 0.0060 mgYellow

EXAMPLE 2

A large scale batch of venlafaxine and risperidone containing tabletswas prepared by mixing 84.86 g of Venlafaxine HCl, 238.83 g of Mannitoland 25.0 g of Povidone. The mixture was wetting with a blend of 120.00ml of alcohol 96°, 22.31 g of Polyethylene Glycol 6000 and 1.50 g ofPolyethylene Glycol 400. The blend was granulated and dried at 40–50° C.for 3 hours; then, it was screened and mixed with 3.00 g of ColloidalSilicon Dioxide. The blend was mixed to homogenize and 4.50 g ofMagnesium Stearate was added as lubricant. The final blend was tablettedusing biconcaves, 9.25-mm diameter punches. Cores weight: 380.0 mg.Hardness from 7 to 12 kp.

A first composition to cover the cores was prepared as follows: 7.53 gof Copolyvidone, 10,50 g of hydroxypropyl methylcellulose 2910, 3.00 gof Polyethylene Glycol 6000 and 3.97 g of Titanium Dioxide in IsopropylAlcohol. This polymer mixture was sprayed onto the tablets in aconventional pan coater to obtain film-coated tablets whose membranecoating weighed 25 mg approximately.

A second composition to cover the film-coated tablets was prepared asfollows: 27.93 g of Cellulose Acetate and 1.47 g of Polyethylene Glycol400 in a mixture of 495 ml of Methylene Chloride and 125 ml of MethylAlcohol. This polymer mixture was sprayed onto the tablets in aconventional pan coater to obtain film-coated tablets whose membranecoating weighed 29.4 mg approximately. A 0.50-mm hole was drilledthrough the coating in one face of the tablet.

The third composition was prepared by mixing 4.39 g of Copolyvidone,3.94 g of Titanium Dioxide, 14.17 g of Talc and 9,00 mg of Aluminum LakeBrilliant Blue in Isopropyl Alcohol.

This polymer mixture was sprayed onto the tablets in a conventional pancoater to obtain film-coated tablets whose membrane coating weighed 15mg approximately.

The rapid release external coating was prepared by mixing 5.00 g ofRisperidone, 381.00 g of Microcrystalline Cellulose, 32.00 g ofPovidone, 20.50 g of Crospovidone and 3.00 g of Colloidal SiliconDioxide. The mixture was blended to homogenize; then, 8.50 g ofMagnesium Stearate was added as lubricant. This blend was tabletted toover the film-coated tablets by compression using biconcaves, 14.0-mmdiameter punches. Coating weight: 450 mg. Hardness from 8 to 12 kp.

The final coating was prepared by mixing 22,68 g of Hydroxypropylmethylcellulose 2910, 6.47 g of Polyethylene Glycol 6000, 8.31 g ofTitanium Dioxide and 45.00 mg of Aluminum Lake Red Ponceau in a mixtureof Methylene Chloride-Alcohol 96° 70:30 v/v (volume/volume). Thispolymer mixture was sprayed onto the tablets in a conventional pancoater to obtain film-coated tablets whose membrane coating weighed 25mg approximately.

Tablets made according to the above procedure generally have thefollowing formulation.

CORE Venlafaxine Hydrochloride 84.860 mg Mannitol 238.830 mg Povidone25.00 mg Polyethylene Glycol 400 1.500 mg Colloidal Silicon Dioxide3.000 mg Polyethylene Glycol 6000 22.310 mg Magnesium Stearate 4.500 mgCOATING A Copolyvidone 7.530 mg Hydroxypropyl methylcellulose 291010.500 mg Polyethylene Glycol 6000 3.000 mg Titanium Dioxide 3.970 mgCOATING B Cellulose Acetate 27.930 mg Polyethylene Glycol 400 1.470 mgCOATING C Copolyvidone 2.925 mg Titanium Dioxide 2.625 mg Talc 9.444 mgAluminum Lake Brilliant Blue 0.006 mg COATING D Risperidone 5.000 mgMicrocrystalline Cellulose 381.000 mg Povidone 32.000 mg Crospovidone20.500 mg Colloidal Silicon Dioxide 3.000 mg Magnesium Stearate 8.500 mgCOATING E Hydroxypropyl methylcellulose 2910 15.120 mg PolyethyleneGlycol 6000 4.310 mg Titanium Dioxide 5.540 mg Aluminum Lake Red Ponceau0.030 mg

EXAMPLE 3

The following general method was used to administer the osmotic deviceof the invention to human patients and to evaluate the performance ofthe osmotic device of the invention to that of the EFFEXOR XR capsule.The bioavailability of the osmotic device was evaluated using atwo-period, single-dose, cross-over randomized pharmacokinetic studywith a one-week washout period using EFFEXOR XR as the control product.Twelve healthy hospitalized subjects (non-smokers between the ages of21–50) were randomly separated into two equally sized groups. The firstgroup received the formulation of Example 1 (75 mg of venlafaxine) andthe second group received the control formulation thirty minutes after anormal breakfast during the first period. After the washout period, thefirst group received the control formulation and the second groupreceived the formulation of Example 1 during a second period. Bloodsamples were taken periodically from 0 to 48 hrs after administrationand plasma aliquots were obtained immediately and stored at −20° C. forlater analysis by HPLC to determine VFX content. The followingpharmacokinetic parameters were calculated from the plasma concentrationcurve for each formulation and each subject: area under the curve from0–48 hrs (AUC_(0-t)) and extrapolated to infinity (AUC_(0-inf)); maximumconcentration of VFX in plasma (C_(max)); and time to reach C_(max)(T_(max)). Safety was evaluated by physical examination, vital signs andadverse event records. Statistical comparisons were made using Analysisof Variance (ANOVA) for the crossover design. Geometric means andclassical 90% confidence intervals for the ratio (test/control) of meanswere calculated in order to evaluate bioequivalence.

EXAMPLE 4

The following general formulation was used to make an osmotic deviceaccording to Example 1, which has a dissolution profile similar to thatdepicted in FIG. 1 and provides a plasma profile similar to thatdepicted in FIG. 2.

Amount INGREDIENT (mg) CORE Venlafaxine (salt or free form)  10–500Osmagent 350–500 Binder  15–100 Plasticizer (lower molecular weight)0.1–50  Glidant 0.1–12  Plasticizer (higher molecular weight)  5–60Lubricant  2–15 COATING A First water soluble polymer  8–15 Second watersoluble polymer  5–25 Plasticizer (higher molecular weight) 0.2–4  Opaquant 0.1–12  COATING B Cellulose ester 40–75 Plasticizer (lowermolecular weight) 0.5–13  COATING C Second water soluble polymer  5–30Third water soluble polymer  3–15 Plasticizer (higher molecular weight)1–6 Opaquant 2–8 First Colorant 0.01–0.1  Second Colorant 0.001–0.05 

EXAMPLE 5

The following general formulation was used to make an osmotic deviceaccording to Example 2, which has a dissolution profile similar to thatdepicted FIG. 1 and provides a plasma profile similar to that depictedin FIG. 2.

INGREDIENT Amount (mg) CORE Venlafaxine (salt or free form)  10–500Osmagent 175–250 Binder 7.5–50  Plasticizer (lower molecular weight)0.1–25  Glidant 0.1–6   Plasticizer (higher molecular weight) 2.5–30 Lubricant   1–7.5 COATING A First water soluble polymer  4–7.5 Secondwater soluble polymer  2.5–12.5 Plasticizer (higher molecular weight)0.1–2   Opaquant 0.1–6   COATING B Cellulose ester   20–37.5 Plasticizer(lower molecular weight) 0.1–6.5 COATING C First water soluble polymer0.5–5   First opaquant 0.1–10  Second opaquant 1.0–15  Colorant0.001–0.05  COATING D Risperidone 0.25–20   Filler 280–500 Binder 15–60Disintegrant 12–70 Glidant 0.1–9   Lubricant 0.5–12  COATING E Secondwater soluble polymer  8–30 Plasticizer (higher molecular weight)0.5–8   Opaquant  2–10 Colorant 0.01–0.05

The above is a detailed description of particular embodiments of theinvention. It is recognized that departures from the disclosedembodiments may be made within the scope of the invention and thatobvious modifications will occur to a person skilled in the art. Thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentswhich are disclosed herein and still obtain a like or similar resultwithout departing from the spirit and scope of the invention. All of theembodiments disclosed and claimed herein can be made and executedwithout undue experimentation in light of the present disclosure.

1. An osmotic device for the delivery of venlafaxine and ananti-psychotic agent comprising: a core comprising a therapeuticallyeffective amount of venlafaxine and at least one osmotic agent orosmopolymer; a semipermeable membrane surrounding the core and having apassageway there through; and an external coat comprising atherapeutically effective amount of an anti-psychotic agent; wherein thecore provides a controlled release of venlafaxine, at least 60% of thevenlafaxine is released in a controlled manner within about 12 hoursafter exposure of the dosage form to an aqueous solution, the externalcoat provides a rapid release of the anti-psychotic agent, and at least75% of the anti-psychotic agent is released within about 1 hour afterexposure of the dosage form to an aqueous solution.
 2. The osmoticdevice of claim 1, wherein the external coat is applied by spraying acomposition onto the semipermeable membrane.
 3. The osmotic device ofclaim 1, wherein the external coat is compressed about and surrounds thesemipermeable membrane.
 4. The osmotic device of claim 1, wherein atleast 75% of the anti-psychotic agent is released within about 40minutes, and at least about 60% of the venlafaxine is released withinabout 10 hours after administration.
 5. The osmotic device of claim 1,wherein the release of at least one of the venlafaxine and theanti-psychotic agent has a delayed onset.
 6. The osmotic device of claim1, wherein the anti-psychotic agent is selected from the groupconsisting of risperidone, olanzapine, clozapine, sertindole,ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone,loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine,chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine,lithium, mesoridazine, spiperone, promazine, prochlorperazine,thioridazine, thiothixene, triflupromazine and raclopride.
 7. Theosmotic device of claim 6, wherein the venlafaxine is administered oncedaily at a dose of 10–500 and the anti-psychotic agent is administeredonce daily at a dose of: a) risperidone—5 to 10 mg per day; b)olanzapine—5 to 20 mg, 0.25–50 mg, 1–30 mg, or 1–25 mg per day; c)clozapine—100 to 400 mg, 12.5–900 mg, or 150–450 mg per day; d)sertindole—15 to 20 mg per day or 0.0001 to 1.0 mg/kg of body weight perday; e) ziprasidone—80 to 160 mg, 5 to 500 mg or 50 to 100 mg pre day;f) quetiapine—150 to 600 mg or 1.0–40 mg/kg of body weight per day; g)sulpiride—50 to 100 mg per day; h) pimozide—2 to 4 mg per day; or i)clothiapine—40 mg per day.
 8. The osmotic device of claim 1, wherein theosmotic device delivers the anti-psychotic agent to the upper GI tractand the venlafaxine to the middle to lower GI tract.
 9. The osmoticdevice of claim 1, wherein the osmotic device provides a venlafaxineC_(max) of about 17–23 ng/ml of plasma in a mammal.
 10. The osmoticdevice of claim 9, wherein the osmotic device provides a venlafaxineT_(max) at about 7–11 hours.
 11. The osmotic device of claim 1, whereinthe osmotic device provides a venlafaxine dissolution profile asfollows: Time (h) Released (%) STD (%) 1 7.2 1.3 3 23.6 0.5 5 43.3 2.1 759.0 2.3 9 69.7 2.1 11 77.0 1.8 13 81.8 1.7 15 84.7 1.7 19 88.1 1.4 23≧90.8 1.5.


12. The osmotic device of claim 11, wherein the osmotic device providesa single-dose venlafaxine plasma concentration profile in a mammal asfollows: Mean venlafaxine Plasma Concentration Time (h) (ng/ml) S.E.M. 00.0 0.0 0.5 0.3 0.2 1 0.4 0.2 2 3.2 0.8 4 13.9 2.6 6 17.5 2.5 8 18.7 2.710 18.8 2.9 12 16.7 2.5 14 15.8 2.7 16 11.8 2.0 20 8.6 1.7 24 6.6 1.1 285.7 1.5 32 3.4 0.7 36 2.2 0.5 48 1.7 0.5.


13. The osmotic device of claim 1, wherein the osmotic device provides avenlafaxine C_(max) of about 20–27 ng/ml of plasma in a mammal.
 14. Theosmotic device of claim 13, wherein the osmotic device provides avenlafaxine T_(max) at about 3.5–8.5 hours.
 15. The osmotic device ofclaim 1, wherein the osmotic device provides a venlafaxine releaseprofile as follows: Time (h) Mean Released (%) S.D. (%) 0 0 0 0.5 0.130.44 1 1.43 1.93 2 10.61 8.37 4 40.48 5.44 6 54.27 4.78 8 63.13 4.67 1066.59 3.36 12 71.44 5.81 14 76.09 5.92 16 77.65 6.58 20 84.94 6.58 24≧89.43 6.48.


16. The osmotic device of claim 15, wherein the osmotic device providesa single-dose venlafaxine plasma concentration profile in a mammal asfollows: Mean venlafaxine Plasma Concentration Time (h) (ng/ml) S.E.M. 00 0 0.5 0.2 0.2 1 1 0.4 2 6 1.6 4 21.2 3.1 6 22.6 3.3 8 21.3 4.0 10 16.82.9 12 15.4 3.3 14 13.4 2.8 16 9.6 1.5 20 8.9 2.5 24 6.5 1.5 28 4.6 1.132 3.7 1.0 36 3.1 0.9 48 1.3 0.3.


17. The osmotic device of claim 1, wherein the osmotic device furthercomprises a first water soluble coat between the core and thesemipermeable membrane.
 18. The osmotic device of claim 17 comprisingthe following ingredients in the approximate amounts indicated: AmountINGREDIENT (mg) Core Venlafaxine (salt or free form)   10–500 Osmagent 350–500 Binder   15–100 Plasticizer (lower molecular weight)  0.1–50Plasticizer (higher molecular weight)   5–60 First water soluble coatFirst water soluble polymer   8–15 Second water soluble polymer   5–25Plasticizer (higher molecular weight)  0.2–4 Semipermeable membraneCellulose ester   40–75 Plasticizer (lower molecular weight)  0.5–13External coat Second water soluble polymer   5–30 Third water solublepolymer   3–15 Plasticizer (higher molecular weight)   1–6.


19. The osmotic device of claim 17 further comprising a second watersoluble coat between the semipermeable membrane and the external coatand an optional exterior finish coat.
 20. The osmotic device of claim 19comprising the following ingredients in the approximate amountsindicated: INGREDIENT Amount (mg) Core Venlafaxine (salt or free form)  10–500 Osmagent  175–250 Binder  7.5–50 Plasticizer (lower molecularweight)  0.1–25 Plasticizer (higher molecular weight)  2.5–30 Firstwater soluble coat First water soluble polymer   4–7.5 Second watersoluble polymer  2.5–12.5 Plasticizer (higher molecular weight)  0.1–2Semipermeable membrane Cellulose ester   20–37.5 Plasticizer (lowermolecular weight)  0.1–6.5 Second water soluble coat First water solublepolymer  0.5–5 First opaquant  0.1–10 Second opaquant  1.0–15 Externalcoat Risperidone 0.25–20 Filler  280–500 Binder   15–60 Disintegrant  12–70 Optional exterior finish coat Second water soluble polymer  8–30 Plasticizer (higher molecular weight)  0.5–8.


21. The osmotic device of claim 1, wherein at least 80% of thevenlafaxine is released in a controlled manner within about 13 hoursafter exposure of the osmotic device to an aqueous solution.
 22. Anosmotic device comprising a first composition comprising atherapeutically effective amount of venlafaxine, and a secondcomposition comprising a therapeutically effective amount of ananti-psychotic agent, wherein the dosage form provides a controlledrelease of venlafaxine and an immediate release of the anti-psychoticagent; at least 60% of the venlafaxine is released in a controlledmanner within about 10 hours after exposure of the dosage form to anaqueous solution; at least 75% of the anti-psychotic agent is releasedwithin about 1 hour after exposure of the dosage form to an aqueoussolution; and the release of at least one of the venlafaxine and theanti-psychotic agent has a delayed onset.
 23. The osmotic device ofclaim 22, wherein the osmotic device delivers the anti-psychotic agentto the upper GI tract and the venlafaxine to the middle to lower GItract.
 24. The osmotic device of claim 22, wherein the osmotic deviceprovides a venlafaxine C_(max) of about 17–23 ng/ml of plasma whenadministered to a mammal.
 25. The osmotic device of claim 24, whereinthe osmotic device provides a venlafaxine T_(max) at about 7–11 hoursafter administration.
 26. The osmotic device of claim 22, wherein theosmotic device provides a venlafaxine C_(max) of about 20–27 ng/ml ofplasma when administered to a mammal.
 27. The osmotic device of claim26, wherein the osmotic device provides a venlafaxine T_(max) at about3.5–8.5 hours after administration.
 28. The osmotic device of any one ofclaims 22, 24 or 26, wherein the anti-psychotic agent is selected fromthe group consisting of risperidone, olanzapine, clozapine, sertindole,ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone,loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine,chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine,lithium, mesoridazine, spiperone, promazine, prochlorperazine,thioridazine, thiothixene, triflupromazine and raclopride.
 29. Anosmotic device comprising a first composition comprising atherapeutically effective amount of venlafaxine, and a secondcomposition comprising a therapeutically effective amount of ananti-psychotic agent, wherein the dosage form provides a controlledrelease of venlafaxine and an immediate release of the anti-psychoticagent; at least 60% of the venlafaxine is released in a controlledmanner within about 12 hours after exposure of the dosage form to anaqueous solution; at least 75% of the anti-psychotic agent is releasedwithin about 1 hour after exposure of the dosage form to an aqueoussolution.
 30. The osmotic device of claim 29, wherein the osmotic devicedelivers the anti-psychotic agent to the upper GI tract and thevenlafaxine to the middle to lower GI tract.
 31. The osmotic device ofclaim 29, wherein the osmotic device provides a venlafaxine C_(max) ofabout 17–23 ng/ml of plasma when administered to a mammal.
 32. Theosmotic device of claim 31, wherein the osmotic device provides avenlafaxine T_(max) at about 7–11 hours after administration.
 33. Theosmotic device of claim 29, wherein the osmotic device provides avenlafaxine C_(max) of about 20–27 ng/ml of plasma when administered toa mammal.
 34. The osmotic device of claim 33, wherein the osmotic deviceprovides a venlafaxine T_(max) at about 3.5–8.5 hours afteradministration.
 35. The osmotic device of any one of claims 29, 31 or33, wherein the anti-psychotic agent is selected from the groupconsisting of risperidone, olanzapine, clozapine, sertindole,ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone,loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine,chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine,lithium, mesoridazine, spiperone, promazine, prochlorperazine,thioridazine, thiothixene, triflupromazine and raclopride.